Circulatory disorders associated with arteriosclerosis including myocardial infarction, cerebral infarction, etc. are increasing yearly and are one of the leading causes of death in adults. There are various causes to induce arteriosclerosis and hyperlipidemia (including hypercholesteremia, hypertriglyceridemia, etc.) is recognized to be one of the most important causes. For the purpose of treating hypercholesteremia, drugs such as HMG-CoA reductase inhibitors (especially, statin type medicaments), anionic exchange resin drugs, etc. have been used. However, these drugs not only inhibit cholesterol biosynthesis but also inhibit the biosynthesis of some other components such as ubiquinone, dolichol and heme A, which are essential for the living body. It is thus concerned that adverse effects caused thereby might take place.
In recent years, the importance of glycosphingolipids (GSLs) in various metabolic disorders (including insulin resistance, type 2 diabetes mellitus, hyperlipidemia, arteriosclerosis, fatty liver, etc.) caused by obesity has been revealed. GSL falls in a molecular group formed by the addition of various sugar chains to the backbone of ceramide and is present in blood or on cell membranes of all cells. GSL is biosynthesized in vivo through a series of enzyme reactions starting from ceramide (FIG. 1). GSL containing sialic acid is called a ganglioside family and starts from GM3 which is synthesized from lactocylceramide (LacCer) by GM3 synthase (sialic acid transferase I: SAT-I) (FIG. 1). Inhibitors to the enzymes involved in biosynthesis of glucosylceramide (GlcCer), which is the early stage of GSL biosynthesis pathway, include: D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) (Non-Patent Document 1), (1R,2R)-nonanoic acid [2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-1-tartaric acid salt (Genz-123346), which is a D-threo-PDMP analog, N-(5-adamantane-1-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), etc. These inhibitors are reported improving insulin resistance in vitro and in obese animal models, having an effect of improving fatty liver and even promoting excretion of free fatty acids (and reducing cholesterol to promote excretion of cholesterol from the liver into the bile (i.e., activation of the reverse cholesterol transport system), etc. (Non-Patent Documents 2 to 7). Thus, development toward clinical applications is ongoing.
However, it is reported that glucosylceramide synthase knockout mice caused embryonic lethality (Non-Patent Document 8) and hence, there is also a concern of potential adverse effects of inhibitors of this enzyme. On the other hand, the life span of GM3 synthase knockout mice is equivalent to that of wild-type mice (Non-Patent Document 9). It is therefore expected that adverse effects caused by inhibition of GM3 synthase may be minimized.
GSLs found in insulin-responsible organs (such as muscle, liver and adipose tissue) are highly diverse and include glucosylceramides (GlcCer), lactosylceramides (LacCer) and gangliosides GM3 and GM2. Yamashita et al. established GM3 synthase (SAT-I) knockout mice and reported that gangliosides of the a- and b-series, which are normally expressed as shown in FIG. 1, were not expressed in the mice, and when the onset of high-fat diet-induced insulin resistance was compared with the onset in the wild-type mice, insulin resistance was reduced in the SAT-I knockout mice (Non-Patent Document 9).    [Non-Patent Document 1] Inokuchi J. & Radin N. (1987) J. Lipid Res. 28, 565-571    [Non-Patent Document 2] Tagami S., Inokuchi J., Kabayama K., Yoshimura H., Kitamura F., Uemura S., Ogawa C., Ishii A., Saito M., Ohtsuka Y., et al. (2002) J. Biol. Chem. 277, 3085-3092    [Non-Patent Document 3] Zhao H., Przybylska M., Wu I. H., Zhang J., Siegel C., Komarnitsky S., Yew N. S., & Cheng S. H. (2007) Diabetes 56, 1210-1218    [Non-Patent Document 4] Zhao H., Przybylska M., Wu I. H., Zhang J., Maniatis P., Pacheco J., Piepenhagen P., Copeland D., Arbeeny C., Shayman J. A., et al. (2009) Hepatology 50, 85-93    [Non-Patent Document 5] Aerts J. M., Ottenhoff R., Powlson A. S., Grefhorst A., van Eijk M., Dubbelhuis P. F., Aten J., Kuipers F., Serlie M. J., Wennekes T., et al. (2007) Diabetes 56, 1341-1349    [Non-Patent Document 6] van Eijk M., Aten J., Bijl N., Ottenhoff R., van Roomen C. P., Dubbelhuis P. F., Seeman I., Ghauharali-van der Vlugt K., Overkleeft H. S., Arbeeny C., et al. (2009) PLoS One 4, e4723. Epub. 2009 March 4723    [Non-Patent Document 7] Bijl N., van Roomen C. P., Triantis V., Sokolovic M., Ottenhoff R., Scheij S., van Eijk M., Boot R. G, Aerts J. M., & Groen A. K. (2009) Hepatology 49, 637-645    [Non-Patent Document 8] YAMASH TA, T., et al, Proc. Natl. Acad. Sci. USA, Vol. 96, pp. 9142-9147, 1999    [Non-Patent Document 9] Yamashita T., Hashiramoto A., Haluzik M., Mizukami H., Beck S., Norton A., Kono M., Tsuji S., Daniotti J. L., Werth N., et al. (2003) Proc. Natl. Acad. Sci. USA 100, 3445-3449